Lymphangiogenesis is considered a promising approach for increasing fluid drainage during secondary
lymphedema. However, organization of lymphatics into functional capillaries may be dependent upon interstitial flow (IF). The present study was undertaken to determine the importance of lymphangiogenesis for
lymphedema resolution. We created a lymphatic obstruction that produces
lymphedema in mouse tail skin. The relatively
scar-free skin regeneration that occurred across the obstruction allowed the progression of lymphangiogenesis to be observed and compared with the evolution of
lymphedema. The role of
vascular endothelial growth factor-C (
VEGF-C)/
VEGF receptor (VEGFR)-3 signaling in
lymphedema resolution was investigated by exogenous administration of
VEGF-C or
neutralizing antibodies against
VEGFR-3.
VEGF-C protein improved
lymphedema at 15 days [reducing dermal thickness from 742 +/- 105 to 559 +/- 141 microm with 95% confidence intervals (CIs), P < 0.05] without increasing lymphatic capillary coverage (11.6 +/- 6.4% following
VEGF-C treatment relative to 9.6 +/- 6.2% with 95% CIs, P > 0.50). Blocking
VEGFR-3 signaling did not inhibit
lymphedema resolution at 25 days (dermal thickness of 462 +/- 127 microm following VEGFR-3 inhibition relative to 502 +/- 87 microm with 95% CIs) or inhibit IF, although
VEGFR-3 blocking prevented lymphangiogenesis (reducing lymphatic coverage to 0.2 +/- 0.7% relative to 8.7 +/- 7.3% with 95% CIs, P < 0.005). A second mouse tail
lymphedema model was employed to investigate the ability of
VEGF-C to increase fluid drainage across a
scar. We found that neither neutralization of
VEGFR-3 nor administration of
VEGF-C affected the course of skin swelling over 25 days. These findings suggest that resolution of
lymphedema in the mouse tail skin may be more dependent upon IF and regeneration of the extracellular matrix across the obstruction than lymphatic capillary regeneration.